7-carboxyphthalides

ABSTRACT

Various derivatives of 8-carboxy-1(2H) phthalazinones are antiinflammatory agents and chemical intermediates for the preparation of 3-keto-2,3-dihydro-1,2,8,9-tetraazaphenalenes.

Umted States Patent [1113,624,108

I721 g: g s2 u.s.c| zoo/343.3. 51] Intel 33Q 73 21 Appl. No. 889,795

[22] Filed Dec. 15,1969

[45] Patented Nov. 30, 1971 7 3 Assignee Geigy Chemical Corporation Ardsley, N.Y.

Original application Apr. 23, 1968, Ser. No. 729,487, now Patent No. 3,539,567,

Continuation-impart of application Ser. No.

583,980, Oct. 3, 1966, now abandoned Continuation-impart of application Ser. No.

539,303, Apr. 1, 1966, now abandoned Continuation-impart of application Ser. No.

445,762, Apr. 5, 1966, now abandoned. Divided and this application Dec. 15, 1969, Ser. No. 889,795

[54] 7-CARBOXYPHTHALIDES 4 Claims, No Drawings [50] Field of Search 260/3433 56] References Cited OTHER REFERENCES Chemical Abstracts- Abstract of Neth. App]. 6604484 (I967). Vol. 66, col. 655 1 7f Primary Examiner-Alex Mazel Assistant Examiner-Bernard l. Dentz Anorneys- Karl F. .lorda, Bruce M. Collins and Martin J.

Spellman. Jr.

7-CARBOXYPHTHALIDES CROSS-REFERENCE pertains to compounds of the formula:

C R \liI R1 in which R is hydrogen, (lower)alkyl, phenyl, or phenyl(lower)-alkyl;

R is hydrogen or phenyl; R is hydrogen, chloro, bromo, hydroxy, (lower)alkoxy, carboxy or nitro; and

R is hydrogen or (lower)alkyl.

The term alkyl" and derivations thereof such as alkoxy" denotes a straight or branched hydrocarbon chain. When qualified by the designation lower), such chain will contain up to and including six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tbutyl, pentyl, hexyl, and the like, while illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, butoxy and the like.

The compounds defined by formula I are useful chemical entities, both having anti-inflammatory activity and being chemical intermediates for the preparation of 3-keto-2,3- dihydro-l ,2,8,9-tetraazaphenalenes, a class of cardiovascular agents described in copending applications Ser. Nos. 583,980, 539,303 and 445,762 referred to above.

The anti-inflammatory properties of these 8-carboxy-l(2 H )phthalazinones can be conveniently observed in standard and accepted tests, recognized by pharmacologists as correlating to a specific therapeutic response. For example, anti-inflammatory activity can be observed in the anticarrageenin study, generally performed in the rat, the ultraviolet erythema antagonism test, generally performed in the guinea pig, and in the adjuvant arthritis test, also performed in the ratv This activity is observed in the dosage range of from about to about 500 mgJkg. of body weight, the precise dosage depending upon the nature, age and size of the species and the particular indication involved. In the use of these compounds as anti-inflammatory agents, standard modes of administration are contemplated such as the unit dosage forms of tablets, capsules, powders, granules, syrups, elixirs and the like.

As mentioned above, these 8-carboxy-l(2H )phthalazinones are also valuable chemical intermediates for the production of 3-keto-2,3-dihydrol ,2,8,9-tetraazaphenalenes. Accordingly, an 8-carboxyl (2H)phthalazinone is heated with hydrazine at reflux temperatures for at least 72 hours in a high boiling ether 75 solvent (one boiling above C.) such as methyl cellosolve, diglyme or triglymc. to yield a 3-keto-2,3-dihydro-l,2,8,9- tetraazaphenalene of formula ll:

R I II The 3-keto-2,3-dihydro-l,2,8,9-tctruazuphcnulcncs of for mula II, as described in said copending applications, are cairdiovascular agents, in particular, blood-pressure lowering agents. They also manifest coronary and peripheral vascular dilation properties and anti-inflammatory activity.

Although the free l(2H)phthalazinone-8-carboxylic acids of formula I R=H) can be used in the above reaction with hydrazine, it is preferable to employ the (lower)alkyl esters [R=] or acid chlorides. Preferred conditions involve the use of hydrazine hydrate in methyl cellosolve.

The 8-carboxy-l(2H)phthalazinones of the present invention are obtained by treating a 3-aldehydophthalic acid, a 3- benzoylphthalic acid, or a functional equivalent of either, with a hydrazine of the formula RNHNH to yield the corresponding 8-carboxyl (2H )phthalazinone:

III

Generally the reaction is easily executed as through heating the reactants, optionally in the presence of a solvent such as alcohol, at temperatures up to about 80 C.

In addition to the 3-carbonylphthalic acids of formula III, various functional equivalents may be employed. For example, in place of the aldehyde function there can be a dibromomethyl group, as in 3-dibromomethylphthalic acid. The aldehyde group can also be in the form of an acetal. Alternatively, or in addition, the carboxylic acid groups can be esterified or be in the form of an anhydride, as in the case of 2- dibromomethyl-6-carbomethoxybenzoic acid or 3- dibromomethylphthalic anhydride. The 3-aldehydoor 3- benzoylphthalic acid can also be in its tautomeric form, a 3- hydroxy-7-carboxy phthalide, optionally bearing a phenyl group in the 3-position. In these phthalides, the hydroxy group in the 3-position can be etherified or replaced by a halogen atom, especially bromo, while the carboxylic acid function can be esterified or in the form of an acid halide, as in the case of 3-bromo-7-chlorocarbonylphthalide.

Thus, among the functional equivalents of the phthalic acids of formula III are compounds of the formulas:

wherein A is an aldehyde, benzoyl, dibromomethyl or dialkoxymethyl group;

each of R and R is alkyl or R" and R taken together are a divalent oxygen atom; and

X is hydroxy, alkoxy, chloro or bromo These important intermediates can be easily prepared via conventional methods. For example, when the known 3- methylphthalic anhydride or substituted analog thereof is treated with at least two equivalents of N-bromosuccinimide under the influence of light, a 3-dibromomethylphthalic anhydride is obtained. Treatment of this anhydride with aqueous base such sodium hydroxide at from to 90, followed by acidification with a mineral acid yields 3-aldehydophthalic acid (which in its tautomeric form is 3-hydroxy-7-carboxyphthalide). Esterification under conventional techniques, e.g., an alkanol and a catalytic amount of acid, yields the dialkyl 3-aldehydophthalate (which in its tautomeric form is 3 hydroxy-7-carboxyphthalide). Esterification under conventional techniques e.g., an alkanol and a catalytic amount of acid, yields the 3-aldehydrophthalate (which in its tautomeric form is 3-alkoxy- 7-carboalkoxyphthalide).

Likewise bromination of a 2-methyl-6-carbalkoxybenzoic acid (obtained through selective esterification of 3- methylphthalic acid) yields the corresponding dibromomethyl-6-carbalkoxybenzoic acid.

In addition a 7-carboxyphthalide (obtained from a 3- bromomethylphthalic anhydride in a fashion analogous to that described above, i.e., successive treatment with base and acid) is converted to the corresponding 7-halo-carbonylphthalide as with phosphorus oxychloride, thionyl chloride or the like and halogenated in the 3-position with an N-halosuccinimide to yield a 3-halo-7-halocarbonylphthalide.

The 8-carboxy-l(2H)phthalazinones of formula I wherein R is hydrogen can also be converted to the corresponding 8- carboxy l( 2H )phthalazinones wherein R is alkyl or phenylalkyl through alkylation, as with an alkyl or phenylalkyl chloride or bromide in aqueous inorganic base or in a lower)alkanol in the presence of alkali hydroxide or alkali alkoxide. In this conversion it is generally preferable to first esterify a free carboxy group in the 8-position, as through formation of the acid chloride and treatment with an alkanol.

A particularly valuable class of compounds are those of formula I wherein R is hydrogen, lower alkyl, phenyl or phenethyl, R is hydrogen or phenyl, R is hydrogen and R is hydrogen, methyl or ethyl.

The following examples will serve to further typify the nature of this invention but should not be construed as a limitatio.n thereof.

EXAMPLE I 3-Dibromomethylphthalic Anhydride A mixture of 3-methylphthalic anhydride (8] g), N- bromosuccinimide (182 g.), benzoyl peroxide (40 mg.) and carbon tetrachloride (1500 ml.) is heated and irradiated at reflux by a l00 Watt insertion-type ultraviolet lamp under stirring and exclusion of moisture. After the mixture becomes brick red, an additional 40 mg. of benzoyl peroxide is added. Illumination at reflux is carried out during 24 hours. The mixture is cooled and filtered free of succinimide and the filtrate is evaporated in vacuo. The residual yellowish brown solid is dissolved in hot ether, treated with decolorizing charcoal and filtered. Addition of hexane to the filtrate affords the crystalline product, 3-dibromomethylphthalic anhydride, m.p. 90.593 C. in 72 percent yield. Two recrystallizations from ether-hexane yield colorless needles melting at 93-95 C.

Calc. for C H4Br O 3- H. -26; B 9- 2; V Found: 33.66; 1.20; 49.4l.

EXAMPLE 2 3-Hydroxy-7-Carboxyphthalide a,aDibromo-3-methylphthalic anhydride 40 g.) is added in portions to a hot solution of 1N sodium hydroxide (500 ml.)

with stirring. After 10 minutes, the clear solution if rendered strongly acidic with concentrated hydrochloric acid and heated for one-half hour at The solution is evaporated to dryness in vacuo and the residue is then dissolved in hot water (600 ml), treated with decolorizing charcoal and filtered. After 3 days at 5 C., the colorless filtrate yields 21.3 g. (88 percent) of colorless blocks of 3-hydroxy-7-carboxyphthalide, m.p. l65.5-l68.5 C., after two further crystallizations from water.

C. $5.68: 55.9ll:

EXAMPLE 3 Calcd: Found:

b. 7-Phthalidylcarbonyl chloride. A mixture of 7-carboxyphthalide (38.54 g.) thionyl chloride (27 ml.) and dry benzene (108 ml.) is heated at reflux with exclusion of moisture for 3 hours. The excess solvent and thionyl chloride are removed by distillation in vacuo and the solid residue is recrystallized from benzene-hexane. The yield of product, m.p. 9296.5 C., is 30.78 g., or 73 percent of theory.

0. 7-Carbethoxyphthalide. 7-Phthalidylcarbonyl chloride (30.78 g.) and absolute ethanol (184.5 ml.) are heated under reflux under moisture exclusion for 30 minutes. The solvent is partially evaporated, whereupon the first crop of product crystallizes. The mother liquors are evaporated in vacuo to dryness, triturated with ethanol and filtered. The two crops are recrystallized from benzene and 23.l g. (65 percent) of product, m.p. 89.5-92.5 C. are obtained. Recrystallization from ethanol yields the pure ester, m.p. 90.5-92 C.

Calcd.

Found:

EXAMPLE 4 Calcd: C, 56.84;

Found: 57.02; 3.15; M115.

B-Carboxy-l(2H)phthalazinone can also be directly obtained from a,a-dibromo-3-methylphthalic anhydride by refluxing with hydrazine hydrate, either 100 percent hydrazine hydrate in chloroform or 50 percent aqueous hydrazine hydrate in ethanol.

EXAMPLE 5 Calcd:

Found:

N, l3.72; I186.

Alternatively, this compound may be made as follows: To a suspension of 8-carboxy-l(2H )phthalazinone (182 g.) in chlorobenzene 1,200 cc.) is added thionyl chloride (250 cc.). This mixture is stirred at reflux with moisture exclusion for 4 hours, cooled and filtered. The white precipitate is washed with benzene, air dried, and suspended in absolute methanol (1,500 cc.). This mixture is heated at reflux under moisture exclusion for 18 hours, cooled to and filtered. The solid thus collected is washed with cold absolute methanol and air dried, m.p. 2l32l5 C.

EXAMPLE 6 8-Carbethoxyl 2H )phthalazinone 3-Bromo-7-carbethoxyphthalide (25.2 g.) is dissolved in absolute ethanol (172 ml.), whereupon a white precipitate forms. 100 percent Hydrazine hydrate (17.25 ml.) in absolute ethanol 172 ml.) is added dropwise with stirring and cooling and the mixture is heated at reflux for 16 hours and then filtered free of the white precipitate. The filtrate is evaporated to dryness in vacuo, triturated with 1N hydrochloric acid (150 ml.) and filtered. The resulting insoluble yellow precipitate and the filtrate are extracted separately with chloroform. The extracts are combined and concentrated in vacuo to a yellow solid (7.15 g. This crude ester is purified by chromatography over neutral alumina and recrystallized from ethanol to yield the product as colorless blocks, m.p. l69.5l7 1 .5 C.

Calcd: C, 60.54; H, 4.62; N, 12.84; Found: 60.54; 4.62; 12.62.

EXAMPLE 7 2-Methyl-8-Carbethoxy- 1 (2H )phthalazinone S-Carbethoxy-l(2l-l)phthalazinone (6 g.) is dissolved almost completely in 2N sodium hydroxide (22 ml.) and water (22 ml.). More water (100 ml.) is added, followed by dimethylsulfate (6 ml.) dropwise under stirring. An oil forms at first but it slowly crystallizes. After 1 hour, the acidic solution is basified with ml. of 2N sodium hydroxide. Methylsulfate (1.8 ml.) is again added dropwise under stirring and the mixture stirred for 16 hours at room temperature. The white precipitate which forms is collected, washed with cold water and dried in vacuo. The filtrate is made slightly basic and extracted several times with chloroform. Concentration of the chloroform layer yields a pale yellow solid whose infrared spectrum is identical to the first crop of material. The first crop is recrystallized from benzene-cyclohexane with the aid of decolorizing carbon in white needles melting in the range l03.5-l05.

The infrared spectrum (chloroform) shows prominent bands at 1,735 cm. (ester carbonyl) and 1,655 cm (amide carbonyl).

Alternatively, compounds of this type, such as 2-methyl-8- carbomethoxy-( 2H )phthalazinone can be prepared via the following procedure: B-Carbomethoxy-l(2H)phthalazinone (2.04 g.) obtained through the use of methanol rather than ethanol in part (c) is dissolved in warm absolute methanol (70 ml.) and treated under stirring with sodium methoxide (0.60 g), whereupon a solution forms. Methyl iodide (0.63 ml.) is added and the whole refluxed under exclusion of moisture for 1 hour, then stirred at room temperature for 16 hours. The orange-yellow solution is evaporated to small volume, treated with warm water and filtered. As the filtrate cools, colorless crystals precipitate from it. The product is collected and washed with cold water. This material, m.p. l l5-12l.5, is purified by two crystallizations from water whereupon it melts at l25l26.

EXAMPLE 8 Calcd. for C 5H N1o; C, 67.66; H. 3.79; N, 10.52

Found: 67.28; 3.75; 10.82

The infrared spectrum (Nujol) shows prominent peaks at 1,720 cm. (carboxyl group) and 1,650 cm. (amide carbonyl).

EXAMPLE 9 2-Phenyl-8-Carbethoxy- 1 2H )Phthalazinone To a solution of thionyl chloride (40 ml.) in chlorobenzene 150 ml.) is added under stirrin'g 8-carboxy-2-phenyl-l (2H )phthalazinone (24.3 g.) and the mixture heated at reflux under moisture exclusion for 2 hours. When the evolution of gas has ceased, the solution is evaporated to dryness in vacuo. The residual white solid (24.7 g.) is treated with absolute ethanol (350 ml.) and heated under reflux for 18 hours. The solution is filtered hot and allowed to cool slowly. The ester precipitates in colorless needles, m.p. l50-l5 1. This materia1 (23.9 g.) is recrystallized from ethanol. The melting point is unchanged.

Culcd. for C H N,O, C, 69.37; H, 4.79; N, 9.52;

Found: 69.08; 4.65; 9.36.

EXAMPLE l0 4-Phenyl-8-Carboxy-1(2H)Phthalazinone 3-Benzoylphthalic acid 32.5 g.) prepared by permanganate oxidation of 2-methyl-6-benzoylbenzoic acid, hydrazine hydrate ml.) and water ml.) are heated at reflux for 18 hours. The mixture is cooled and rendered acidic with hydrochloric acid. The solid which precipitates is recrystallized from glacial acetic acid to yield 4-phenyl-8-carboxy-l (2H)phthalazinone, m.p. 257259.

Calcd. for C HmN O I C. 67.66; H, 3.79; N, I052; 4 Found: 67.87; 3.68; 10.82.

EXAMPLE I l 4-Phenyl-8-Carbomethoxyl 2H )Phthalazinone EXAMPLE l2 2-(2-Phenethyl)-8-Carboxy 1 (2H )Phthalazinone To a mixture of anhydrous sodium acetate (28.4 g.) glacial acetic acid (1,300 ml.) and Z-phenethylhydrazine sulfate (26.0 g.) is added 3-hydroxy-7-carboxyphthalide (l9.4 g.). The mixture is stirred at reflux for 18 hours, filtered hot and evaporated to dryness. The residue is triturated with chloroform and the chloroform layer is extracted with 5 percent sodium carbonate solution. The alkaline extracts are cautiously rendered acidic with 6N hydrochloric acid and the material which precipitates is extracted with chloroform. The dried chloroform extracts are evaporated to dryness and the residue is taken up in boiling benzene, filtered and slowly treated with hexane. The white precipitate which forms is collected, washed with hexane and dried. The product (m.p. ll5-l23) can be further purified through recrystallization from ethanol-water. (m.p. l l9-l 22 C).

Calcd. for C H N,O,: C 69.37;

Found: 69.40;

EXAMPLE l3 Calcd. for c..H,,N,o c, 70.1 1; a, 5.23; N, 9.09; Found: 70.00; 5.23; 8.95.

EXAMPLE 1 4 2-lsopropyl-8-Carbomethoxyl (2H )Phthalazinone 8-Carbomethoxy- 1 (2H )phthalazinone (20.4 g.) is

suspended in methanol (250 ml.) and treated with a mixture of 2-iodopropane l7 g.),-1N sodium hydroxide (100 ml.) and methanol (I ml.). This mixture is stirred on the steam bath for 3 hours and then evaporated to dryness at reduced pressure and recrystallized from methanol to yield the product.

EXAMPLE l 2-Ethyl-8-Carbethoxy- 1 (2H )Phthalazinone B-Carbethoxy-l(2H)phthalazinone (3.0 g.) is dissolved in 2N sodium hydroxide l 1.0 ml.). Water (60 ml.) is added, followed by diethylsulfate (4.2 ml.) dropwise under stirring. The mixture is stirred 60 hours at room temperature and then brought to pH 4 with a few drops of 2N sodium hydroxide. The mixture is stirred 2 hours longer, and the oily mixture extracted with chloroform. The chloroform layer is dried over sodium sulfate and concentrated in vacuo. The product is purified by distillation in a Spaeth apparatus at 0.03 mm. with an air bath temperature of 160. The LR. spectrum of the product in chloroform reveals strong bands at l,735 cm? (ester carbonyl) and L655 cm (amide carbonyl).

EXAMPLE l6 3-Keto-2,3-Dihydrol ,2,8,9-Tetraazaphenalene A solution of B-carbomethoxy-l(2H)phthalazinone L02 g.), prepared as in example 5, in I00 percent hydrazine hydrate (5 ml.) and absolute ethanol (20 ml.) is heated at reflux for hours, then is cooled and filtered. The precipitate is washed with water, then methanol and dried in vacuo. The yield of 3-keto-2,3-dihydro- 1 ,2,8,9- tetraazaphenalene, m.p. 350 C. is 0.78 g., or 84 percent of theory.

EXAMPLE l7 3-keto-9-Methyl-2,3-Dihydrol ,2,8,9-Tetraazaphenalene To a solution of hydrazine hydrate (5 ml.) in methyl-cellosolve (20 ml.) is added 2-methyl-8-carbethyoxy-l (2H)phthalazinone (I. I6 g.), prepared as in example 7. The whole is stirred at reflux for 26 hours, during which time a yellow solution forms. The solution is filtered hot and the filtrate allowed to cool under refrigeration. The yellow crystals which precipitate are collected, washed with methanol and dried. The mother liquor is evaporated to dryness in vacuo and the residue triturated with hot methanol and filtered. The precipitate is a second crop of the product. The combined material, m.p. 300-304, (386 mg.) is recrystallized from methyl cellosolve and the pure product obtained in bright yellow needles, melting at 305306.

Calcd. for C,.,H,.N.0; c, 59.99; H. 4.03; N. 21.99;

Found; 59.91; 4.18; 25.12.

EXAMPLE l8 The infrared spectrum (Nujol) shows a strong amide carbonyl band at 1,650 emf.

In a similar fashion from 2isopropyl-8-carbomethoxy-l (2H )phthalazinone, there is obtained 3-keto-9-isopropyl-2,3- dihydrol ,2,8,9-tetraazaphenalene, m.p. 258-259 C.

Calcd. for C H EXAMPLE l9 3-Keto-9-Phenyl-2,3Dihydro-l ,2,8,9-Tetraazaphenalene A mixture of 2-phenyl-8-carbethoxy-l(2H)phthalazinone (ll.76 g.) prepared as in example 9, I00 percent hydrazine hydrate (40 ml.) and methyl cellosolve ml.) is heated at reflux for 25 hours. The yellow solution is filtered and treated with methanol (100 ml.) followed by water dropwise under stirring. A flocculent yellow precipitate forms. The mixture is cooled and the product collected, washed thoroughly with water and ethanol and dried in vacuo. The solid (4.44 g. m.p. 2546, is recrystallized from methyl cellosolve and obtained as yellow needles, m.p. 2557.

Calcd. for C H N O: C. 68.70; H. 3.85; N, 2|.37;

Found: ($3.8M 3.90; 21.20.

EXAMPLE 2O 3-Keto-9-( 2-Phenethyl)-2,3-Dihydro 1 ,2,8,9- Tetraazaphenalene A mixture of 2-(2-phenethyl)-8-carbomethoxy-l(2l-l)pht.h

alazinone (32.5 g.), 100 percent hydrazine hydrate (400 cc.)

and water (70 cc.) is stirred at reflux for 20 hours and then cooled. The yellow precipitate is collected, washed thoroughly with water, air dried, and recrystallized twice from chloroform to afford the product, m.p. 203- Calcd. for C H N O: C. 703 2; Ml- 3 6; l1, i9 3); Found: 70.]3, 4.87; l9.33.

EXAMPLE 2] 3-Keto-7-Phenyl-2,3-Dihydro-l ,2,8,9-Tetraazaphenalene A mixture of 4-phenyl-8-carbomethoxy-l (2H)phthalazinone 18.6 g.), hydrazine hydrate (400 cc.) and water 100 cc.) is heated at reflux for 20 hours. The mixture is cooled and the precipitate is collected, washed with water and recrystallized from methyl cellosolve to yield the product, m.p. above 350 C.

Calcd. for C H,,N.O: C, 68.70; H, 3.85;

Found: 68.89; 3.62; .39.

EXAMPLE 22 3-Keto-2,3-Dihydrol ,2,8,9-Tetraazaphenalene A suspension of a,a-dibromo-3-methylphthalic anhydride (80 g.) in ethanol (500 ml.) is treated with a solution of 100 percent hydrazine hydrate (lQO ml.) and water (100 ml.) dropwise under stirring and cooling. A white suspension forms. After the addition, the temperature is raised gradually to reflux, whereupon the white suspension disappears and a yellow precipitate forms. After 88 hours at reflux, the mixture is cooled, filtered and the first crop of product is washed with water and ethanol and dried in vacuo. The mother liquors are evaporated in vacuo. dissolved in 500 ml. of glacial acetic acid and heated under reflux for 18 hours. The mixture is cooled and filtered and a second crop of the product obtained. The overall yield of 3-keto-2.3-dihydro-l ,2,8,9-tetrauzuphenulene. m.p. 347, is 25.7 g., or 55 percent of theory. The product is recrystallized from 3 liters of boiling dimethyltormamide and obtained as a yellow powder which, on heating. forms a microcrystalline solid at 220-270 C. and melts above 350 C.

wherein R is hydrogen or phenyl and each of X and X is hydroxy, chloro, bromo or lower alkoxy.

2. A compound according to claim 1 which is a 3-alkoxy-7- carboalkoxyphthalicle.

3. The compound according to claim 1 which is 3-bromo-7- carboxyphthalide.

4. A compound according to claim I which in 3-bromo-7- chlorocarbonylphthalide.

l I! I! i 

2. A compound according to claim 1 which is a 3-alkoxy-7-carboalkoxyphthalide.
 3. The compound according to claim 1 which is 3-bromo-7-carboxyphthalide.
 4. A compound accOrding to claim 1 which in 3-bromo-7-chlorocarbonylphthalide. 